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Downey, M.

Publications and source records attributed to Downey, M..

2 recordsLinked to original sources
bioRxiv2018

Targeting MYC Overexpressing Leukemia with Cardiac Glycoside Proscillaridin Through Downregulation of Histone Acetyltransferases

Targeting MYC oncogene remains a major therapeutic goal in cancer chemotherapy. Here, we demonstrate that proscillaridin, a cardiac glycoside approved for heart failure treatment exhibit anticancer selectivity towards high MYC expressing leukemic cell lines and leukemia stem cells. At a clinically relevant concentration, proscillaridin induced a rapid downregulation of MYC protein level, due to a significant decrease in MYC protein half-life. Proscillaridin treatment induced a downregulation of gene sets involved in MYC pathway, and a concomitant upregulation of genes involved in hematopoietic differentiation. Proscillaridin induced a significant loss of lysine acetylation in histone H3 (K9, K14, K18 and K27) and in non-histone proteins such as MYC, MYC target proteins, and a series of histone acetylation regulators. Loss of lysine acetylation correlated with a rapid downregulation of histone acetyltransferase protein levels, involved in histone and MYC acetylation (CBP, P300, GCN5, TIP60, and MOZ), preferentially in MYC overexpressing leukemia as compared to other cancer cells. These results support the repurposing of proscillaridin in MYC overexpressing leukemia and propose a novel strategy to target MYC in cancer.

pharmacology and toxicology↗
bioRxiv2018

A synthetic non-histone substrate provides insight into substrate targeting by the Gcn5 HAT and sirtuin HDACs

Gcn5 and sirtuins are highly conserved HAT and HDAC enzymes that were first characterised as regulators of gene expression. Although histone tails are important substrates of these enzymes, these proteins also target many non-histone substrates that participate in diverse biological processes. The mechanisms used by these enzymes to choose their non-histone substrates is unclear. In this work, we use a unique synthetic biology approach in S. cerevisiae to demonstrate that a shared target sequence can act as a determinant of substrate selection for Gcn5 and sirtuins. We also exploit this system to define specific subunits of the Gcn5-containing ADA complex as regulators of non-histone acetylations proteome-wide.

molecular biology↗